Hepatitis C virus (HCV) infection is a global human health problem with approximately 150,000 new reported cases each year in the United States alone. HCV is a single stranded RNA virus, which is the etiological agent identified in most cases of non-A, non-B post-transfusion and post-transplant hepatitis and is a common cause of acute sporadic hepatitis. It is estimated that more than 50% of patients infected with HCV become chronically infected and 20% of those develop cirrhosis of the liver within 20 years.
Several types of interferons, in particular, alfa-interferons are approved for the treatment of chronic HCV, e.g., interferon-alfa-2a (ROFERON®-A), interferon-alfa-2b (INTRON®-A), consensus interferon (INFERGEN®), as well as pegylated forms of these and other interferons like pegylated interferon alfa-2a (PEGASYS®) and pegylated interferon alfa-2b (PEG-INTRON®). Most patients are unresponsive to interferon-alfa treatment, however, and among the responders, there is a high recurrence rate within 6 months after cessation of treatment (Liang et al., J. Med. Virol. 40:69, 1993).
Ribavirin, a guanosine analog with broad spectrum activity against many RNA and DNA viruses, has been shown in clinical trials to be effective against chronic HCV infection when used in combination with interferon-alfas (see, e.g., Poynard et al., Lancet 352:1426-1432, 1998; Reichard et al., Lancet 351:83-87, 1998), and this combination therapy has been approved for the treatment of HCV: REBETRON® (interferon alfa-2b plus ribavirin, Schering-Plough); PEGASYS®RBV® (pegylated interferon alfa-2a plus ribavirin combination therapy, Roche); see also Manns et al, Lancet 358:958-965 (2001) and Fried et al., 2002, N. Engl. J. Med. 347:975-982. However, even with this combination therapy the virologic response rate is still at or below 50%.
Furthermore, there are significant side-effects typically associated with such therapies. Ribavirin suffers from disadvantages that include teratogenic activity, interference with sperm development, haemolysis, fatigue, headache, insomnia, nausea and/or anorexia. Interferon alfa, with or without ribavirin, is associated with many side effects. During treatment, patients must be monitored carefully for flu-like symptoms, depression, rashes and abnormal blood counts. Patients treated with interferon alfa-2b plus ribavirin should not have complications of serious liver dysfunction and such subjects are only considered for treatment of hepatitis C in carefully monitored studies.
Certain interferon-containing combination therapies for treating HCV infection are also disclosed in the following U.S. Patent Application Publications: US 2005/0112093; US 2005/0129659; and US 2008/0138316.
The following Compound (1):
is known as a selective and potent inhibitor of the HCV NS3 serine protease and useful in the treatment of HCV infection. The bonding is significant for showing a particular stereochemistry of the compound. Compound (1) falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Pat. Nos. 6,323,180, 7,514,557 and 7,585,845. Compound (1) is disclosed specifically as Compound #1055 in U.S. Pat. No. 7,585,845, and as Compound #1008 in U.S. Pat. No. 7,514,557. Compound (1), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety. Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form, which can be prepared as described in the examples section herein.
Compound (1) may also be known by the following alternate depiction of its chemical structure, which is equivalent to the above-described structure:
wherein B is
L0 is MeO—; L1 is Br; and R2 is

Although Compound (1) has been found generally effective in the reduction of viral load and the treatment of HCV infection, a certain amount of viral resistance with resulting viral rebound has been seen. For example, we have observed with Compound (1) given once-daily to treatment-naive patients as monotherapy for 14 days a strong and very rapid antiviral affect followed by a certain amount of resistance formation after 5-6 days.
Therefore, there is a continuing need in the field for alternative therapies for the treatment and prevention of HCV infection.